Modified sequential oral contraceptive

ABSTRACT

This invention relates to new modified sequential oral contraceptive preparations and a method of administering them. According to this invention a regimen is followed in which a combination of estrogen and a low amount of progestogen is administered for the first 14 to 19 day phase of the cycle and a combination of estrogen and a high amount of progestogen is administered for the succeeding 4 to 7 day phase of the cycle. A 25 to 28 day cycle is completed with a 5 to 7 day hormone-free phase which may include the use of placebos or iron and/or vitamin supplement.

United States Patent Leonard Joseph Lerner [72] Inventor New Brunswick,NJ. [21] Appl. No. 619,562 [22] Filed Mar. 1,1967 [45] Patented Mar. 9,1971 [73] Assignee E. R. Squibb & Sons, Inc.

New York, N.Y.

[54] MODIFIED SEQUENTIAL ORAL CONTRACEPTIVE 5 Claims, No Drawings [52]US. Cl 206/42, 424/2, 424/6, 424/ 14 1 424/239, 424/240, 206/56, 116/121[51] Int. Cl A6lj 7/00 [50] Field ofSearch 167/55, 74 (Con), (Der WentForm Doc); 424/147, 240, 243; 239; 206/42, 56(A3); 116/121 [56]References Cited UNITED STATES PATENTS 3,409,721 11/1968 Applezweig424/239 3,075,882 1/1963 Sponnoble et al. 167/74 3,143,207 8/1964 Wagner206/42 3,182,791 5/1965 Jenner..... 206/56 3,193,457 7/1965 Kincl 167/553,230,142 1/1966 Spero 167/55 3,269,910 8/1966 lrmscher 424/238 FOREIGNPATENTS 992,160 5/1965 Great Britain.

OTHER REFERENCES Lerner et al., Proc. Soc., Exp. Biol. Med., vol. 106,(1961 pp. 231- 234.

British Medical Journal, vol. 2, No. 5405, August 1964, pp. 357. 358.

New Drugs, American Medical Association, Chicago, 111., (received July1966), (1966), pp. 379-384.

Primary ExaminerShep K. Rose Attorneys-Lawrence S. Levinson, Merle J.Smith and Theodore J. Criares ABSTRACT: This invention relates to newmodified sequential oral contraceptive preparations and a method ofadministering them. According to this invention a regimen is followed inwhich a combination of estrogen and a low amount of progestogen isadministered for the first 14 to 19 day phase of the cycle and acombination of estrogen and a high amount of progestogen is administeredfor the succeeding 4 to 7 day phase of the cycle. A 25 to 28 day cycleis completed with a 5 to 7 day hormone-free phase which may include theuse of placebos or iron and/or vitamin supplement.

MODWIED SEQUENTIAL ORAL CONTRACEPTIVE This invention relates to amodified sequential oral contraceptive.

Oral contraceptives currently accepted are of two types. Both dependupon the administration to the nonpregnant female of a progestogen andan estrogen. In one type, which is the combination type, both aprogestogen and an estrogen are prescribed for daily use over a periodof 20 or 21 days, followed by a to 7 day period when neither is taken,to allow for a bleeding phase, then the combination is resumed. Theprogestogen level is fairly high. This establishes a 25 to 28 day cycle.

The second, sequential type, also establishes a 25 to 28 day cycle butin the first phase of to 16 days only an estrogen is ingested, then inthe second 5 or 6 day phase a combination of progestogen and estrogen,as in the combination type, is taken. A blank period of 5 to 7 days whenneither type of steroid is taken, to allow for a bleeding period, alsocompletes this 25 to 28 cycle.

While both types have proven quite effective, each offers certaindisadvantages. With the combined hormone therapy, the uterine histologydoes not resemble the normal-proliferative or secretory picture innormal cycling" women. Instead the endometrium is ofa mixed typegenerally described as pseudopregnant. There is also some incidence ofamenorrhea and many women do not return to normal cycles for many monthsafter discontinuing the use of the contraceptive combination. The highcost of progestogen is also a factor.

The sequential type of administration is somewhat closer to the sequenceof physiological ovarian secretion, but two separate types of tabletsmust be taken in proper sequence and this is confusing to some. Moreimportantly, estrogen prepares the uterus for ova implantation inaddition to inhibiting pituitary gonadotrophins. This requires strictadherence to the daily dosage schedule since deviation from the 24 hourinterval of medication may result in a surge of gonadotrophin leading toovulation and increased possibility of fertilization and pregnancy. 7

It is an object of this invention to provide a modified contraceptiveretaining the advantages of both types and overcoming disadvantages.

According to this invention, progestogen and estrogen are administeredthroughout the 20 or 23 day therapy period. However, in the initial 14to 19 day phase the amount of progestogen is sharply decreased from theamount currently supplied in the combination type of contraceptive. Thenin the succeeding 4 to 7 day phase estrogen plus a high amount ofprogestogen is used. Then there is a 5 to 7 day bleeding period whenthere is no hormone administered or alternatively, a placebo or ironand/or vitamin supplement is taken to institute a one-a-day regimenduring the complete 25 to 28 day cycle in order to reduce patientfailure as described in my copendi'ng application Ser. No. 483,859,filed Aug. 30, 1965, now abandoned.

Thus the dosage regimen for this combination is 14 to 19 days ofestrogen low dose of progestogen, then 7 to 4 days of estrogen high doseof progestogen followed by 5 to 7 days of no therapy or placebo or ironfor a 28 day repeating cycle. Typical variations of the days in eachphase of the cycle, preferably of 28 day duration, include, for example,14 7 7,16+5 +7, l9+4+5, l7+6+5, l8+5+5. Thelowdose of progestogen in thefirst phase will tend to prevent pregnancy even if a tablet is missed bythe effect of progestogen on ova transport, prevention of reboundphenomena induced by withdrawal of estrogen inhibition and thesuppressive effect upon ovarian steroidogenesis not seen with treatmentwith either type of steroid alone.

The large amount of progestogen in the second 4 to 7 day phase is toinsure an adequate buildup of endometrium to allow for a more effectivedesquamation upon withdrawal of hormone treatment.

The estrogen component of the oral contraceptive regimen is generallyadministered in an amount of 0.05 to 0.1 mg. daily throughout the 20 to21 day period of therapy within the 25 to 28 day cycle. According tothis invention, the low amount of progestogen combined with the estrogenduring the initial 14 to 19 day phase of the cycle is about 0.25 toabout 20 mg. The high amount of progestogen combined with the estrogenduring the second 4 to 7 phase of the cycle is then increased to about 2to 200 mg.

In speaking of low and high amounts of progestogen, it will beappreciated that these are related to the potency of the particularprogestogen selected. Progestational agents which are effective inconventional contraceptive preparations are administered in amounts ofabout 1 to 25 mg. per day depending upon their potency. Thus in speakingof a low amount it is intended that about 10 to about 25 percent of thatamount which would be administered according to prevailing practice inthe currently used combination type of preparation or of that amountused in the second phase of the cycle. Similarly, the high dosage is theamount of progestogen required daily for an adequate development of asecretory endometrium preparatory to desquamation, i.e., in the range ofabout 2 to 250 mg. The low dosage of a given progestogen is insufficientto adequately produce this condition and may be regarded as a subpotentamount.

Thus, for example, if chlormadinone acetate is used as the progestogen,this highly potent substance would be used according to conventionalpractice in an amount of about 3 mg. per day. According to thisinvention, about 0.25 to 0.5 mg. of chlormaclinone is used in the firstor low phase and about 2 to 5 mg. in the second or high phase.

Similarly, l6a,l7a-dihydroxyprogesterone acetophenonide, a less potentprogestational agent, is conventionally used at a dosage of about 50 to250 mg. per day. According to this invention, the initial low amount isabout 10 to 20 mg. per day and the later high dosage is about 50 to 200mg. per day. The estrogens similarly vary in potency and are usedaccording to this invention in the range of about 0.05 to 0.1 mg. (perday), preferably 0.075 to 0.1 mg in both phases.

The contraceptives of this invention may be made up by conventionalprocedures in any form for oral administration, capsules, tablets andthe like, but tablets are the preferred mode of administration.

The dosage units are preferably packaged in a dispensing device, e.g., afolder or sequential plastic dispenser, and arranged in a manner whichfacilitates the orderly daily administration in sequence and aids thewoman in keeping track of her regimen. Color variations may be used asan aid in this I respect. I

In order to provide further aid in maintaining the regimen, the 21 to 23tablets or capsules containing the hormones may be followed with asequence of 5 to 7 similar placebo units, or units containing an ironand/or vitamin supplement for use during the nontherapy bleeding portionof the cycle to complete the 28 day period. In this manner, a tablet orcapsule is taken every day and it is easier to keep track of theschedule and maintain regularity.

Estrogens which may be used according to this invention includel7a-ethynylestradiol 3-methyl ether, 17-ethinylestradiol and any otherorally active estrogen.

Progestogens include ethynodiol diacetate, megestrol acetate,l6a,l7a-dihydroxyprogesterone acetophenonide, 1?- hydroxyl 9-norl7a-pregn-5( l0 )-en-20-yl-3-one, 19'norl7a-pregn-4-en-20-yne-3B,17-diol,l7-hydroxyl 9-nor- 1 7apregn-4 -en-20-yl-3-one and its acetate,l7-hydroxy-6amethyl-pregn-4-ene-3,20-dione and its acetate, 601,21-dimethyl-l 7-hydroxy-pregn-4-en-20-yne-3-one,6-chlorol7a-hydroxy-pregna-4,6-diene-3 ,ZO-dione, 9B, 1 Our-pregna-4,l6-diene-3,20-dione, and any other orally active progestogen.

A preferred regimen includes 14 tablets containing 5 to 20 mg. of1601,l7a-dihydroxyprogesterone acetophenonide 75 to mcg. of ethinylestradiol followed by 7 tablets containing 25 to 50 mg. ofl6a,l7oz-dihydroxyprogesterone acetophenonide 75 to 100 mcg. of ethinylestradiol. This may be followed by 7 placebo tablets or 7 tablets eachcontaining supplemental iron in any of the conventionally availableforms, e.g., 5 to 50 mg. daily (as elemental iron), with or without amaintenance multivitamin formula of conventional constitution includingvitamins A, B complex, C, D, etc.

The following examples are illustrative of the invention.

EXAMPLE 1 a. 1,000 capsules are prepared from the following ingredients:

1 604,1 7a-dihydroxyprogesterone acetophenonide m. inyl estradiolLactose 326 gm.

Talc 10.5 gm.

Magnesium stearate 3.5 gm.

The ethinyl estradiol is dissolved in chloroform and dispersed on thelactose, then let dry. This is admixed with the acetophenonide, talc andmagnesium stearate. The mixture is subdivided and filled into 1000 No. 2red gelatin capsules each containing 10 mg. of the acetophenonide and 75mcg. of ethinyl estradiol.

b. 1,000 No. 2 uncolored capsules are prepared from the same ingredientsas in part (a) except that 50 gm. of 1601,1704- dihydroxyprogesteroneacetophenonide and 286 gm. of lactose are used. Each capsule contains 50mg. of the acetophenonide and 75 mcg. of ethinyl estradiol. Fourteencapsules from part (a) and capsules from part (b) are placed inindividual, plastic covered compartments in rows in a folder withdirections to take one per day of the red capsules for 14 days beginningwith day 5 from onset of menstruation and then one per day of the whitecapsules for 7 days.

EXAMPLE 2 a. 1,000 tablets of 90 mg. each are prepared from thefollowing ingredients:

g Eth 75 mg.

Mestranol 80 mg. Chlormadinone 500 mg. Spray dried lactose 43.52 kg.

Microcrystalline cellulose (Avicel) 45.0 kg. Stearic acid 900 mg. Themestranol and chlormadinone are dissolved in chloroform. The solution ispoured onto the microscrystalline cellulose while mixing, then this isallowed to dry. The dried mixture, lactose and stearic acid are blended,then compressed into tablets using a fia-inch standard concave die. Thetablets are undercoated with shellac, dried and pan coated with FD & CRed No. 3. Each tablet contains 0.5 mg. ofchlormadinone and 80 mcg. ofmestranol.

b. 1,000 tablets of 90 mg. each are prepared from the same ingredientsas in part (a) except that 3 grams of chlormadinone and 41.02 kg. ofspray dried lactose are used. The tablets are left uncoated. Eachcontains 3 mg. of chlormadinone and 80 mcg. of mestranol.

Nineteen tablets from part (a) and 4 tablets from part (b) are placed insequence in a plastic dispenser dispensing one tablet at a time withdirections as in example 1 except for appropriate changes in the numberof days to 19 and 4, respectively.

EXAMPLE 3 day for 5 days following the white tablets.

EXAMPLE 4 One thousand tablets of 145 mg. each are prepared from thefollowing ingredients:

Ferrous sulfate 25 gm. Sucrose gm. Lactose 20 gm.

The above materials are granulated with 3 percent of a polyvinylpyrrolidone-alcohol solution, dried and admixed with 3 percent by weightof starch and 1 percent by weight of stearic acid, then compressed andcoated as in example 2 (FD & C Blue No. 1). Five of these iron tabletsare used in place of the placebos in example 3.

lclaim:

1. A packaged sequential combination of contraceptive composition whichcomprises unit dosage forms for oral administration of one unit dosageform daily in sequence during a 25 to 28 day cycle, each of the first 14to 19 of said unit dosage forms comprising as the essential components afirst phase combination of estrogen in a daily dosage amount of from 0.5mg. to 0.1 mg., said amount preparing the uterus for ova implantation inaddition to inhibiting pituitary gonadotrophins, which daily estrogendosage if omitted during a 24 hour interval may result in a surge ofgonadotrophin leading to ovulation, with a subpotent dosage of a givenspecies of progestogen, each of the next 4 to 7 unit dosage formscomprising as the essential components a second phase combination ofestrogen with an increased dosage of progestogen, the amount of the samespecies of progestogen in the initial 14 to 19 unit dosage forms beingabout 10 to about 25 percent of the amount in each of the subsequent 4to 7 unit dosage forms, said daily sequential unit dosages being placedin consecutive sequence in individual covered compartments in adispensing package bearing direction to take one per day and adapted fordispensing one at a time each day, said subpotent, first phase dosagesof a given species of progestogen being insufficient to adequatelyproduce the development of a secretory endometrium and tending toprevent pregnancy if a daily dosage is missed by the effect ofprogestogen on ova transport, prevention of rebound phenomena induced bywithdrawal of estrogen inhibition and suppressive effect on ovariansteroidogenesis not seen with treatment with either type of steroidalone, said second phase high dosages of the same species of progestogenbeing the amount required daily for insuring an adequate development ofa secretory endometrium preparatory to desquamation upon withdrawal ofhormone treatment.

2. A combination of tablets as in claim 1 comprising a first series of14 to 19 tablets each containing about 0.05 to about 0.1 mg. of estrogenand about 0.25 to about 20 mg. of progestogen and a second series of 4to 7 tablets each containing about 0.05 to about 0.1 mg. of estrogen andabout 2 to about 200 mg. of progestogen.

3. A combination of tablets as in claim 1 wherein the first 14 to 19tablets contain about 75 mcg. of ethinyl estradiol and about 10 mg. of.1601, l 7a-dihydroxyprogesterone acetophenonide and the next 4 to 7tablets contain about 75 mcg. of ethinyl estradiol and about 50 mg. ofl6a,l7a-dihydroxyprogesterone acetophenonide.

4. A combination of tablets as in claim 3 wherein the first 14 to 19tablets contain about 75 mcg. of ethinyl estradiol and about 10 mg. of1601,17a-dihydroxyprogesterone acetophenonide, the next 4 to 7 tabletscontain about 75 mcg. of ethinyl estradiol and about 50 mg. of1601,]7a-dihydroxyprogesterone acetophenonide and a third series of 5 to7 tablets to complete the 25 to 28 unit cycle contains about 5 to 50 mg.of iron in each.

5. A combination as in claim 1 wherein an additional 4 to 7 unit dosageform comprises iron supplement or nonmcdicinal ingredients.

2. A combination of tablets as in claim 1 comprising a first series of14 to 19 tablets each containing about 0.05 to about 0.1 mg. of estrogenand about 0.25 to about 20 mg. of progestogen and a second series of 4to 7 tablets each containing about 0.05 to about 0.1 mg. of estrogen andabout 2 to about 200 mg. of progestogen.
 3. A combination of tablets asin claim 1 wherein the first 14 to 19 tablets contain about 75 mcg. ofethinyl estradiol and about 10 mg. of 16 Alpha ,17 Alpha-dihydroxyprogesterone acetophenonide and the next 4 to 7 tabletscontain about 75 mcg. of ethinyl estradiol and about 50 mg. of 16 Alpha,17 Alpha -dihydroxyprogesterone acetophenonide.
 4. A combination oftablets as in claim 3 wherein the first 14 to 19 tablets contain about75 mcg. of ethinyl estradiol and about 10 mg. of 16 Alpha ,17 Alpha-dihydroxyprogesterone acetophenonide, the next 4 to 7 tablets containabout 75 mcg. of ethinyl estradiol and about 50 mg. of 16 Alpha ,17Alpha -dihydroxyprogesterone acetophenonide and a third series of 5 to 7tablets to complete the 25 to 28 unit cycle contains about 5 to 50 mg.of iron in each.
 5. A combination as in claim 1 wherein an additional 4to 7 unit dosage form comprises iron supplement or nonmedicinalingredients.